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Epimización acoplada del grupo metilo y reducción por los dominios de la cetorreductaza de la sintetasa policetida.

Ashish Garg¹, Chaitan Khosla, David E Cane

¹Department of Chemistry, Brown University , Providence, Rhode Island 02912-9108, United States.

Journal of the American Chemical Society

|October 29, 2013

Resumen

Los dominios específicos de la ketorreductaza en las sintetasas policetidas poseen actividad epimerasa intrínseca. Este descubrimiento ayuda a comprender los mecanismos detrás de la estereocomplejidad poliquetídica.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
Química orgánica es la química orgánica.

Sus antecedentes:

Las poliquetidas sintasas (PKS) son cruciales para sintetizar productos naturales complejos.
Se sabe que los dominios de la cetorreductaza (KR) dentro de la PKS controlan la estereoquímica.
Las actividades enzimáticas precisas de los dominios PKS KR no están completamente aclaradas.

Objetivo del estudio:

Para investigar la actividad potencial de epimerasa de los dominios específicos de la PKS cetorreductaza.
Comprender el papel de los dominios KR en la generación de la diversidad estereocímica en las policetidas.
Desarrollar métodos para el análisis mecanicista de los dominios PKS KR.

Principales métodos:

Etiquetado por isótopos de deuterio de los precursores de los policeturos.
Incubación de sustratos etiquetados con dominios de cetorreductaza purificados.
Análisis del lavado de deuterio utilizando técnicas analíticas (por ejemplo, espectrometría de masas).

Principales resultados:

La epimerización de los dominios de la cetorreductaza (EryKR1, RifKR7, NysKR1) demostró un lavado de deuterio dependiente del tiempo y del cofactor de sustratos específicos.
Los dominios de cetorreductazas no epimerizantes (EryKR6, TylKR1) no mostraron un lavado de deuterio significativo.
El lavado de deuterio observado se atribuye al intercambio de isótopos de equilibrio.

Conclusiones:

Los dominios específicos de la cetorreductaza de la poliquetida sintasa poseen actividad epimerasa intrínseca.
Esta actividad epimerasa es un determinante clave de la complejidad estereoquímica de la policetida.
El ensayo de intercambio de isótopos proporciona un método directo para identificar y estudiar la actividad de la epimerasa PKS.

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